Polyfluorinated and perfluorinated chemicals (PFCs) are environmentally persistent, detectible across a wide range in almost every American, and linked to worrisome health outcomes in human and animal studies including developmental toxicities, cancers, and thyroid dysfunction. Less consistent evidence also links higher levels of PFCs with risk factors for cardiometabolic disease including higher body mass index (BMI), cholesterol, and metabolic syndrome as well as type 2 diabetes mellitus. However, many prior studies were limited by small sample sizes, reliance on mortality data, and/or weaker designs including cross sectional and case-control rather than prospective cohort studies. We propose to evaluate longitudinal associations of PFCs with detailed cardio-metabolic risk measures in a large, well-characterized population of adults who are at high risk for developing type 2 diabetes and cardiovascular disease (CVD). We will study over 1000 participants enrolled in the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPPOS) who have stored baseline and follow-up plasma samples available for analysis. These participants with baseline impaired glucose tolerance were randomized to an intensive lifestyle (ILS) intervention (n=637) or to a placebo-treated control group (n=398), and have been followed for 15 years or more. At least annually, outcomes potentially sensitive to PFCs have been assessed including: adiposity, blood pressure, lipids, glycemia, and conversion to type 2 diabetes. The use of this randomized trial cohort will also allow for effect modification analysis in which we will investigate whether intervention effects (ILS vs. placebo) on weight change and diabetes risk differ by PFC exposure level. This project will leverage the unparalleled resources of the DPPOS to assess, for the first time ever within this highly productive cohort, the contribution of synthetic chemicas to adiposity, diabetes, and other CVD risks. By adding PFC measures, we have an exceptionally cost-effective opportunity to conduct 15+ years of analysis over just a 5-year grant cycle.